As many as one-third of the approximate 3,000 known genetic disorders are believed to have important neurological involvement. Individually, most genetic disorders are of low incidence in the general population; however, collectively they represent an enormous burden on affected individuals, their families, and society. Many neurogenetic disorders manifest themselves early in life leading to either a premature death or to lifelong disability with significant attendant psychological and economic hardships.
Examples of these types of disorders include: (1) Hereditary ataxias and related disorders such as Friedreich ataxia, ataxia telangiectasia, olivopontine cerebellar degeneration, Ramsay Hunt syndrome, abetalipoproteinemia, Machado-Joseph disease, and familial spastic paraparesis; (2) Movement disorders such as Juvenile Huntington disease, the dystonias including blepharospasm and spasmodic torticolis, tremor, myoclonus, and Hallervorden-Spatz disease; (3) Phakomatoses, or neurocutaneous syndromes such as neurofibromatosis, tuberous sclerosis, Sturge-Weber, and Von Hippel-Landau disease; (4) Mitochondrial encephalomyopathies such as the MELAS syndrome, Kearns-Sayre, and Leigh disease; (5) Hereditary disorders of nerve and muscle such as infantile spinal muscular atrophy, Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathies, genetic myasthenic syndromes, metabolic myopathies, muscular dystrophies, and myotonias.
There are numerous other neurological disorders that are also believed to result from genetic abnormalities such as the Laurence-Moon-Bardet-Biedl, Aicardi, Sjogren-Larsson, Prader-Willi and Angelman syndromes.
In addition to those diseases that have a recognizable pattern of inheritance, there are many other neurological disorders that seem to have, in some cases, a familial basis. These may well represent neurogenetic disorders with multifactorial etiology. Such diseases can be as diverse as disorders of defective cellular migration (such as lissencephaly, heterotopias), neural tube defects, congenital hydrocephalus, myoclonic epilepsy, attention deficit hyperactivity disorder (ADHD), and narcolepsy.
It is estimated that ADHD affects about 4% to 6% of the U.S. population. ADHD is not limited to children and is a chronic lifetime disease. Approximately one-half to two-thirds of children with ADHD will continue to have significant problems in adulthood and experience difficulties which impact employment, familial, and social relationships.
According to the DSM-IV (the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) some common symptoms of ADHD include: (1) often fails to give close attention to details or makes careless mistakes; (2) often has difficulty sustaining attention to tasks; (3) often does not seem to listen when spoken to directly; (4) often fails to follow instructions carefully and completely; (5) losing or forgetting important things; (6) feeling restless, often fidgeting with hands or feet, or squirming; (7) running or climbing excessively; (8) often talks excessively; (9) often blurts out answers before hearing the whole question; and (10) often has difficulty awaiting turn. It should be kept in mind that the exact nature and severity of ADHD symptoms varies from person to person however. Approximately one-third of people with ADHD do not have the hyperactive or overactive behavior component.
To meet diagnostic criteria, these behaviors must be excessive, long-term, and pervasive. The behaviors must appear before age 7, and continue for at least 6 months. A crucial element requires that the behaviors must create a real handicap in at least two areas of a person's life, such as school, home, work, or social settings. These criteria set ADHD apart from the “normal” distractibility and impulsive behavior of childhood, or the effects of the hectic and overstressed lifestyle prevalent in our society.
There are no reports in the literature of topiramate specifically used to treat deficits in attention and concentration. Carbamazepine (Tegretol) has been reported to be useful for the treatment of patients experiencing sudden confusion and depression. Within weeks of initiating treatment, the patients experienced fewer incidences of sudden confusion and depression, and an increase in attention and focus. Persinger, M. A., “Subjective improvement following treatment with carbamazepine (Tegretol) for a subpopulation of patients with traumatic brain injuries”, Percept Mot Skills 90:37-40 (2000). Carbamazepine has also been shown to be effective in treating children with features of ADHD. Silva, R. R.; Munoz, D. M.; Alpert, M., “Carbamazepine use in children and adolescents with features of attention-deficit hyperactivity disorder: a meta-analysis”, J Am Acad Child Adolesc Psychiatry 35:352-358 (1996). In some patients, with or without intellectual disability, being treated for refractory partial epilepsy, gabapentin is an equally effective add-on medication. Mikati, M. A.; Choueri, R.; Khurana, D. S.; et al., “Gabapentin in the treatment of refractory partial epilepsy in children with intellectual disability”, J Intellect Disabil Res 42:57-62 (suppl. 1, 1998). Three dementia patients are noted in the literature to have received topiramate in a retrospective chart review of 58 consecutive psychiatric patients receiving topiramate. Marcotte, D., “Use of topiramate, a new anti-epileptic as a mood stabilizer”, J Affect Disorder 50:245-251 (1998). “Improvement” was rated by a Likert scale from ‘worse,’ to ‘no change,’ to ‘minimally improved,’ to ‘moderately improved,’ to ‘markedly improved.’ The three patients with dementia are described to have ‘moderate’ or ‘marked’ improvement when on topiramate. The author of this chart review hypothesized that topiramate may have some anti-psychotic effect.
While there have been no reported efforts to use topiramate for the treatment of impulsivity, there have been a limited number of publications reporting the effects of anti-convulsant treatment on impulsivity (or measures of impulsivity). These references tend to show no change or worsening of impulsivity with anti-convulsant treatment. For example, one large study showed no overall effect on measures of impulsivity of anti-convulsant medication in epileptic children (Mitchell, W. G.; Zhou, Y.; Chavez, J. M.; Guzman, B. L., “Reaction time, attention, and impulsivity in epilepsy”, Pediatr Neurol 8:19-24 (1992)) and another large study showed, at higher total serum levels of anti-convulsant medication in children with epilepsy, more impulsive errors on complex reaction time testing (Mitchell, W. G.; Zhou. Y.; Chavez, J. M.; Guzman, B. L., “Effects of anti-epileptic drugs on reaction time, attention, and impulsivity in children”, Pediatrics 91:101-105 (1993)). It is notable that both of these studies focused on children with epilepsy.
A case report from 1987 described carbamazepine being useful for intermittent explosive disorder in a patient with Prader-Willi Syndrome (Gupta, B. K.; Fish, D. N.; Yerevanian, B. I., “Carbamazepine for intermittent explosive disorder in a Prader-Willi syndrome patient”, J Clin Psychiatry 48:423 (1987)). Carbamazepine has also been reported useful in the treatment of pathological gambling (Haller, R.; Hinterhuber, H., “Treatment of pathological gambling with carbamazepine”, Pharmacopsychiatry 27:129 (1994)). There are also reports in the literature of divalproex being effective for explosive mood and mood lability (Donovan, S. J.; Stewart, J. W.; Nunes, E. V.; Quitkin, F. M.; Parides, M.; Daniel, W.; Susser, Klein D. F., “Divalproex treatment for youth with explosive temper and mood lability: a double-blind, placebo-controlled crossover design”, Am J Psychiatry 157:818-820 (2000)) and for a patient with kleptomania and mixed mania (Kmetz, G. F.; McElroy, S. L.; Collin, D. J., “Response of kleptomania and mixed mania to valproate”, Am J Psychiatry 154:580-581 (1997)).
Prader-Willi Syndrome (PWS) is a neurogenetic multisystem disorder characterized by infantile hypotonia, mental retardation, short stature, hypogonadism, dysmorphic features, and hyperphagia with a high risk of obesity. Also very common in PWS are behavioral and psychiatric manifestations. These include self-injury (e.g. gouging, nail biting, and skin picking), explosive outbursts, oppositional behavior, obsessive ruminations, and compulsive behaviors including hoarding, counting, and arranging. PWS is typically a sporadic condition, which usually results from a deletion in chromosome 15q11-q13 or maternal uniparental disomy of chromosome 15. Glenn, C. G.; Driscoll, D. J.; Thomas, P. Y.; Nicholls, R. D., “Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes”, Mol Hum Reprod 3:321-332 (1997).
PWS is also a relatively common genetic condition with an estimated prevalence of approximately 1/10,000 to 1/25,000. Glenn, C. G.; Driscoll, D. J.; Thomas, P. Y.; Nicholls, R. D., “Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes”, Mol Hum Reprod 3:321-332 (1997). It was first described in 1956 (Prader, A.; Labhart, A.; Willi, H., “Ein Syndrome von adipositas, Kleinwuchs, Kryptorchismus und Oligophrenic nach myoteniertigem zusland in neugeborenanalter”, Schwiez Med Wschr 86:1260-1 (1956)), and the physical problems (such as the obesity related cardiovascular diseases, diabetes mellitus, etc.) and behavioral problems result in the major causes of morbidity and mortality. Martin, A.; Matthew, S.; Koenig, K.; et al., “Prader-Willi syndrome”, Am J Psychiatry 155:1265-1273 (1998).
Treatment for the physical, behavioral, and psychological problems associated with PWS is complex. The mainstay of treatment for behavioral problems including hyperphagia is behavioral modification including strategies such as token economies or star systems. Dykens, E. M.; Hodapp, R. M., “Treatment issues in genetic mental retardation syndromes”, Professional Psychology: Research and Practice 28:263-270 (1997). Additionally, medication management of individuals with PWS has been demonstrated to have benefit. Growth hormone therapy in children with PWS can increase muscle tone and enhance growth. Carrel, A. L.; Myers, S. C.; Whitman, B. Y.; et al., “Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study”, J Pediatr 134:215-221 (1999); Lindgren, A. C.; Hagenas, L.; Muller, J.; et al., “Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report”, The Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl 423:60-62 (1997). Therefore, growth hormone can help to normalize body habitus. Martin, A.; Matthew, S.; Koenig, K.; et al., “Prader-Willi syndrome”, Am J Psychiatry 155:1265-1273 (1998); Carrel, A. L.; Myers, S. C.; Whitman, B. Y.; et al., “Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study”, J Pediatr 134:215-221 (1999); Lindgren, A. C.; Hagenas, L.; Muller, J.; et al., “Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report”, The Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl 423:60-62 (1997). In terms of obesity, the anorectic fenfluramine was shown to be helpful for weight loss and aggressive behavior in PWS utilizing a double-blind placebo-controlled trial. Selikowitz, M.; Sunman, J.; Pendergast, A.; et al., “Fenfluramine in Prader-Willi syndrome: a double-blind, placebo controlled trial”, Arch Dis Childhood 65:112-114 (1990). Unfortunately due to cardiovascular consequences, fenfluramine is not now currently available. There are few studies of anorectic agents in PWS and anecdotal reports have been discouraging in terms of their benefits. Martin, A.; Matthew, S.; Koenig, K.; et al., “Prader-Willi syndrome”, Am J Psychiatry 155:1265-1273 (1998).
Pathological skin picking (PSP) is a severe and chronic psychiatric and dermatologic problem with an average age of onset around 15 years of age and mean duration of illness of 21 years. Keuthen, W. S.; Deckersbach, T.; Engelhard, I. M.; et al., “Self-injurious skin picking: clinical characteristics and comorbidity”, J Clin Psychiatry 60:454-459 (1999). PSP can lead to significant suffering, dysfunction, and disfigurement. Ko, S. M., “Under-diagnosed psychiatric syndrome II: Pathologic skin picking”, Ann Acad Med Singapore 28:557-559 (1999). Furthermore, there is often psychiatric comorbidity. Keuthen, W. S.; Deckersbach, T.; Engelhard, I. M.; et al., “Self-injurious skin picking: clinical characteristics and comorbidity”, J Clin Psychiatry 60:454-459 (1999). PSP is often considered an obsessive compulsive spectrum disorder (Goldsmith, T. D.; Shapira, N. A.; Phillips, K. A.; et al., “Obsessive Compulsive Spectrum Disorders”; in: Swinson, R. P.; Antony, M. M.; Rachman, S.; Richter, M. A. (Eds)., Obsessive-Compulsive Disorder. Theory, Research, and Treatment, Guilford Publications, New York, pp. 397-425 (1998)) and, as such, there are several reports of serotonin receptor inhibitors (SSRI) medication being helpful. Ko, S. M., “Under-diagnosed psychiatric syndrome II: Pathologic skin picking”, Ann Acad Med Singapore 28:557-559 (1999).
The literature points to topiramate having a negative impact on cognitive functioning including impaired concentration, attention, memory, slowed thinking, word finding, and verbal fluency. Thompson, P. J.; Baxendale, S. A.; Duncan, J. S.; et al.; “Effects of topiramate on cognitive function”, J Neurol Neurosurg Psychiatry 69:636-641 (2000); Privitera, M.; Fincham, R.; Penry, J.; et al., “Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages”, Topiramate YE Study Group. Neurology 46:1678-1683 (1996); Crawford, P., “An audit of topiramate use in a general neurology clinic”, Seizure 7:207-211 (1998); Jones, M. W., “Topiramate—safety and tolerability”, Can J Neurol Sci 25:S13-15 (1998); Burton, L. A.; Harden, C., “Effect of topiramate on attention”, Epilepsy Res 27:29-32 (1997); Martin, R.; Kuzniecky, R.; Ho, S. “Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults”, Neurology 52:321 (1999); Fraught, E.; Wilder, B. J.; Ramsay, R. E.; et al., “Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages,” Neurology 46:1684-1690 (1996); and Rosenfeld, W. E.; Liao, S.; Kramer, L. D.; et al., “Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy”, Epilelpsia 38:324-333 (1997). A few studies have systematically looked at cognitive changes using neuropsychological testing. In one study (Burton, L. A.; Harden, C., “Effect of topiramate on attention”, Epilepsy Res 27:29-32 (1997)), 10 adult patients with epilepsy were evaluated weekly for up to 13 weeks via a digit span test. In 4 patients, there was an inverse correlation between topiramate does and test performance. In another study, healthy volunteers were treated with topiramate, gabapentin, or lamotrigine for 4 weeks. Impaired cognitive functioning (attention and word fluency) was seen in the topiramate treated subjects and not in gabapentin or lamotrigine in these healthy young adults. Martin, R.; Kuzniecky, R.; Ho, S. “Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults”, Neurology 52:321 (1999). Finally, in a recent study of 18 epilepsy patients treated with topiramate and receiving repeat neuropsychological assessments, patients on topiramate showed significant deterioration in many cognitive domains, including verbal IQ, verbal fluency, and verbal learning. Thompson, P. J.; Baxendale, S. A.; Duncan, J. S.; et al.; “Effects of topiramate on cognitive function“, J Neurol Neurosurg Psychiatry 69:636-641 (2000). Improvement in verbal fluency, verbal learning, and digit span increased in patients where topiramate was withdrawn or reduced.
The subject invention has, surprisingly, found improvements in impulsivity control, without negative effects on attention and concentration, in patients treated with topiramate. These observations are unexpected and novel.